Dysmenorrhea or menstrual pain is the most common of all gynecological disorders in thirty to forty percent of postpubescent females. Though the etiology of primary dysmenorrhea has not been established, it is known that dysmenorrheic subjects show evidence of a higher prostaglandin activity in their menstrual fluid. It is also known that prostaglandins have a powerful uterine stimulating activity, and many researchers believe that dysmenorrhea and menstrual pain from abnormal uterine muscle contraction are associated with the higher prostaglandin levels in dysmenorrhea subjects. Continued or prolonged dysmenorrhea may result in more severe disorders such as endometriosis.
In general, non-sterioldal anti-inflammatory agents prevent the synthesis of prostaglandins and thus find some use in relieving pain in primary dysmenorrhea, but these drugs also prolong the bleeding time, due to their inhibition of platelet aggregation time. Other classes of drugs, e.g. anticholinergics and tranquilizers have found little use in this disorder.
Amidinoureas are known to have a variety of pharmacological effects and in particular, certain substitued amidinoureas are disclosed in U.S. Pat. No. 4,115,647 as having the property of producing a considerable spasmolytic action on the gastrointestinal musculature. Other amidinoureas have been described in U.S. Pat. No. 4,060,635 as having anti-diarrheal properties which implies an antimotility effect related to spasmolytic action on the gastrointestinal musculature.
It has now unexpectedly been found that certain amidinoureas possess valuable pharmacological properties and these compounds exhibit an unexpected capability of inhibiting oxytocin and prostaglandin-induced contractions in In Vitro preparations. Abnormal uterine muscle contractions during the menstrual cycle in dysmenorrhea subjects are due to elevated levels of prostaglandin, therefore, certain amidinoureas will be efficacious in the treatment of dysmenorrhea. Unlike known anti-diarrheal agents that are generally available, such as diphenoxylate hydrochloride and loperamide, which are not effective in the treatment of dysmenorrhea, the amidinoureas appear to exert their activity on uterine muscle by acting beyond the prostaglandin receptor sites in a more fundamental way within the muscle membrane or contractile fiber which makes them particularly useful in the treatment of muscle spasms associated with primary dysmenorrhea. Depending on the particular situation, these amidinoureas may also inhibit prostaglandin-induced diarrhea, which at times accompanies dysmenorrhea.
It has also been found that these amidinoureas, which are easily absorbed from the stomach, have a low order of toxicity so that orally administering amidinoureas to females provides a simple and effective method for preventing and treating dysmenorrhea. Further, in accordance with this invention, a therapeutic program of treatment with an amidinourea can be the basis for relief from the pain of primary dysmenorrhea or, if started early in females having a tendency towards dysmenorrhea, amidinoureas administered continually in effective amounts can prevent the development of endometriosis and other severe conditions resulting from repeated dysmenorrhea.